title: Phase II, open-label trial to assess QTcF effects, pharmacokinetics and antitumor activity of afatinib in patients with relapsed or refractory solid tumors.
abstract: OBJECTIVE
  Afatinib is an irreversible ErbB family blocker currently under evaluation in late-stage clinical trials. This study primarily assessed the cardiac safety, pharmacokinetics and antitumor activity of afatinib in cancer patients.
  
  
  METHODS
  In this multicenter, Phase II, open-label, single-arm trial, 60 patients with solid tumors who were expected to express epidermal growth factor receptor-1 and HER2 received oral afatinib 50 mg daily. QTcF intervals (QT interval corrected by the Fridericia formula) were evaluated based on electrocardiogram recordings time-matched with pharmacokinetic blood samples after single (Day 1) and continuous (Day 14; steady state) administration. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0; antitumor activity was assessed using RECIST 1.0.
  
  
  RESULTS
  There was a nonsignificant decrease of 0.3 ms (90 % confidence interval -2.8, 2.3; N = 49) in the mean of the average time-matched QTcF interval from baseline to steady state. The maximum plasma concentration for afatinib was seen at median tmax 3 h after both single dose and at steady state. No relationship between afatinib plasma concentrations and time-matched QTcF, QT and heart rate change was found. The overall adverse event profile was consistent with the known safety profile of afatinib. One patient demonstrated a partial response (PR) and two patients unconfirmed PRs.
  
  
  CONCLUSIONS
  Afatinib had no impact on cardiac repolarization, had a manageable safety profile and demonstrated antitumor activity in this uncontrolled study.
authors.affiliation: Drug Development Unit, The Royal Marsden Hospital, Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK, rhoda.molife@icr.ac.uk.
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Rudman
authors.forename: Salma
authors.initials: S
authors.lastname: Alam
authors.forename: Daniel S-W
authors.initials: DS
authors.lastname: Tan
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kristeleit
authors.forename: Gary
authors.initials: G
authors.lastname: Middleton
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.forename: Liz
authors.initials: L
authors.lastname: Bent
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.forename: Gudrun
authors.initials: G
authors.lastname: Wallenstein
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: James
authors.initials: J
authors.lastname: Spicer
mesh_terms: D000284:Administration, Oral; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004562:Electrocardiography; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human